Abstract By 2030, 72 million Americans will be over the age of 65 and of those almost 9 million will be over the age of 85. Frailty is a recognized and important geriatric syndrome that results in a decline across multiple interrelated systems that confer a loss of reserve in response to stressors, such as acute health care events. The frailty syndrome is highly associated with hospitalization, institutionalization, morbidity and mortality. Disability due to declining functional health status associated with frailty is and will become an increasing burden at a clinical, financial, and social level. A complex interaction exists between physical frailty, cardiovascular disease (CVD), and cognitive impairment. Individuals with CVD have a high prevalence of frailty, and frail adults with CVD have significantly worse outcomes than individuals with CVD alone. Physical frailty is a risk factor for cognitive impairment, and frailty-related vascular risk factors are also associated with increased Alzheimer's disease incidence and prevalence. An understanding of the interaction between cardiovascular disease, cognitive impairment and physical frailty has remained predominantly at an epidemiological level, limiting the ability to understand mechanisms and develop targets for intervention. The proposed research looks to determine specific hemodynamic and vascular changes associated with the longitudinal progression of the frailty syndrome. In Aim 1, I will relate hemodynamic abnormalities assessed by cardiac MRI (i.e., arterial vascular stiffness and impaired left ventricular filling reflective of changes in ventricular-arterial coupling) to the longitudinal progression of frailty (as measured by change in composite frailty score) over 36 months. In Aim 2, I will relate hemodynamic abnormalities to the longitudinal progression of a proposed intermediate marker of frailty (change in skeletal muscle quality as measured by quantitative MRI thigh muscle analysis) from baseline to 36 months. In Aim 3, I will relate hemodynamic abnormalities (as assessed by cardiac MRI) and frailty status (as an effect modifier) to longitudinal change in neuropsychological function over the 36-month follow-up period. I propose that this research offers a unique methodological innovation that will significantly advance the field on a physiological and mechanistic level. The collective result of this work will be the possible development of an interventional study targeted toward reducing frailty that focuses on cardiovascular factors.